1. Field of the Invention
The present invention relates to a method of treating chemical dependency using .beta.-carboline alkaloids, derivatives, and salts thereof.
2. Description of the Background
One class of plant indole alkaloids is the .beta.-carboline alkaloids. There are presently 64 known .beta.-carboline alkaloids dispersed throughout at least eight plant families. Schultes, R. E. et al., The Botany and Chemistry of Hallucinogens, C. C. Thomas, Springfield, Ill. All of the .beta.-carboline alkaloids share a three ring nucleus designated 4-carboline by Perkin and Robinson. Organic Chemistry: An Advanced Treatise, Gilman (John Wiley and Sons, 1943). The first alkaloids of this class isolated were harmine and harmaline.
Harmine was first isolated from Peganum harmala seeds by Fritsche in 1847 (Bestandtheile der samen von Peganum harmala, Annalen 64:360-364), while harmaline was first isolated by Goegel in 1841 (In German, Isolation of Harmalol & Harmaline form Peganum harmala, Annalen 38:363 et seq.) A simplified extraction method using acetic acid was published by Hasenfratz in 1927 (In German, Extraction of Harmine and Harmaline from Peganum harmala, Ann. Chim. Phys. 10(7):151). Not until 1919, however, was the structure of harmaline established by Perkin and Robinson.
Thereafter, harmaline was first synthesized and its structure elucidated by Manske et al. (Manske RHF, Perkin, W. H., Robinson R, 1927, Part IX. Synthesis of harmaline, Jour. Chem. Soc. London, 1-15). Other syntheses of harmine and harmaline were accomplished by Akabori & Saito (1930, Synthesis of Harman and Harmine, Bericht 63:2245-2249); Spath and Lederer (1930, Synthese der Harmala alkaloids: Harmalin, Harmin, und Harman, Bericht 63:120-125); and Spencer (1959, A synthesis of Harmaline, Canadian Jour. Chem. 37:1851-1858).
One of the earliest reviews of the physiological activity of harmaline was that of Gunn, who proposed that harmaline be used to treat Malaria, (1909, Trans. Royal Soc. Edinburgh 47:245f). Similar assertions were subsequently made for harmine in 1911 (Trans. Royal Soc. Edinburgh 48:83f). In 1928, the efficacy of the harmala alkaloids to treat Parkinson's disease was noted, (1928, Uber ein neues auf das extrapyramidal-motorische system wirkendes alkaloid (Banisterine), Der Nervennarzt. 1:265-275).
Later, Chen et al established the LD 50 for harmine in mice and rabbits and further determined that sodium barbital limited toxicity (1939, Harmine, the Alkaloid of Caapi, Quart. Jour. Pharm. Pharmacol. 12:30-38). This paper additionally reviewed the pharmacology of known .beta.-carboline alkaloids. Further contributions to the understanding of the harmala alkaloids were made by Gunn et 1935. Relations between Chemical Constitution, Pharmacological Actions, and Therapeutic Uses in the Harmine Group of Alkaloids; Arch. lnt'l. Pharmacodyn. Ther. 50:379-396).
More recently, it was demonstrated that harmaline is a monoamine oxidase inhibitor (Udenfriend S, Witcop B, Redfield B. G., Weissbach H, 1958, Studies with reversible inhibitors of monoamine oxidase: Harmaline and Related Compounds, Biochem. Pharmacol. 1:160-165). Lamarre et al. defined the cerebellar activity of harmaline in 1971 (Lamarre Y. et al, Harmaline-Induced Rhythmic Activity of Cerebellar and Lower Brain Stem Neurons, Brain Res. 32:246-250). In 1973, further studies of the physiological effects of harmaline were provided. (Harmaline-Induced Rhythmic Activity of Alpha and Gamma Motoneurons in the Cat, Brain Res. 63:430-434).
Even more recently, Singh et al ascertained neurotransmission and neurohormonal effects of harmaline. Further, harmaline, as a monoamine oxidase inhibitor, was shown to have an effect upon the concentration of dopamine and serotonin in the striatum of the cat with and without unilateral brainstem lesions, Canad. J. Physiol. Pharmacol. 45:897-904). However, the opposite effects of harmaline on serotonin and on dopamine and its metabolites, homovanillic acid and norepinephrine, in the brain of the cat, has also been noted, Canad. J. Physiol. Pharmacol. 46:585-589). Klein & Rowe studied the relationship of harmine, melatonin and serotonin (1970, Pineal gland in organ culture: Harmine Inhibition of Serotonin-C14 Oxidation is Accompanied by Stimulation of Melatonin-C14 Production, Mol. Pharmacol.6:164171). Given and Longenecker evaluated binding of harmine to human platelets (1983, Tetrahydroisoquinolines and .beta.-carbolines: specific binding to human platelet alpha 2-receptors in vitro, Res. Commun. Chem. Pathol. Pharmacol. 41(2):349-352).
Clarification of the relationship of the harmala alkaloids and benzodiazepine receptors were presented by Robertson et al. (1981, Interactions of .beta.-carbolines with the Benzodiazepine Receptor, Structure Activity Relationships, Eur. J. Pharmacol. 76:281) and by Rommelspacher et al. (1981, Benzodiazepine Antagonism by Harmine and Other .beta.-carbolines In Vitro and In Vivo, Eur. J. Pharmacol. 70:409).
The effects of harmaline in psychotherapy were evaluated by Naranjo. (1969, Psychotherapeutic possibilities of new fantasy-enhancing drugs, Clin. Toxicol. 2(2):209-224). See also The Healing Journey (1975, 124-173, Harmaline and the collective unconscious, Pantheon Books, N.Y.).
Finally, a review of the field and the development of harmine from an historical and medical perspective is provided by Sanchez-Ramos. (1991, Banesterine and Parkinson's Disease, Clinical Neuropharmacology 14(5):391-401).
Thus, to date, harmine and harmaline have been used largely in physiological, particularly neurological, laboratory investigations. However, little attention has been given to clinical uses thereof.
At the same time, chemical dependencies continue unabated among all age groups, with neither young nor old persons being immune from chemical dependency disorders, abuse syndromes or combinations thereof. Presently, relatively "benign" drugs, such as methadone, are administered to persons as a substitute for drugs, such as heroin. However, this approach is only intended to minimize the adverse effects of drug withdrawal and does not reduce the underlying craving for the drug. Generally, efforts to date to combat drug abuse have focused on minimizing withdrawal symptoms. Little, or nothing, has been done to minimize craving for addictive substances.
Accordingly, it would be quite desirable if a compound or composition were known which, upon administration, afforded a reduced craving for a substance which causes chemical dependency disorders, abuse syndromes or a combination thereof in mammals.